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Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming
BACKGROUND: A multitude of recent studies has observed common epigenetic changes develop in tumour cells of multiple lineages following exposure to stresses such as hypoxia, chemotherapeutics, immunotherapy or targeted therapies. A significant increase in the transcriptionally repressive mark trimet...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408861/ https://www.ncbi.nlm.nih.gov/pubmed/30850015 http://dx.doi.org/10.1186/s13148-019-0644-y |
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author | Torrano, Joachim Al Emran, Abdullah Hammerlindl, Heinz Schaider, Helmut |
author_facet | Torrano, Joachim Al Emran, Abdullah Hammerlindl, Heinz Schaider, Helmut |
author_sort | Torrano, Joachim |
collection | PubMed |
description | BACKGROUND: A multitude of recent studies has observed common epigenetic changes develop in tumour cells of multiple lineages following exposure to stresses such as hypoxia, chemotherapeutics, immunotherapy or targeted therapies. A significant increase in the transcriptionally repressive mark trimethylated H3K9 (H3K9me3) is becoming associated with treatment-resistant phenotypes suggesting upstream mechanisms may be a good target for therapy. We have reported that the increase in H3K9me3 is derived from the methyltransferases SETDB1 and SETDB2 following treatment in melanoma, lung, breast and colorectal cancer cell lines, as well as melanoma patient data. Other groups have observed a number of characteristics such as epigenetic remodelling, increased interferon signalling, cell cycle inhibition and apoptotic resistance that have also been reported by us suggesting these independent studies are investigating similar or identical phenomena. MAIN BODY: Firstly, this review introduces reports of therapy-induced reprogramming in cancer populations with highly similar slow-cycling phenotypes that suggest a role for both IFN signalling and epigenetic remodelling in the acquisition of drug tolerance. We then describe plausible connections between the type 1 IFN pathway, slow-cycling phenotypes and these epigenetic mechanisms before reviewing recent evidence on the roles of SETDB1 and SETDB2, alongside their product H3K9me3, in treatment-induced reprogramming and promotion of drug resistance. The potential mechanisms for the activation of SETDB1 and SETDB2 and how they might arise in treatment is also discussed mechanistically, with a focus on their putative induction by inflammatory signalling. Moreover, we theorise their timely role in attenuating inflammation after their activation in order to promote a more resilient phenotype through homeostatic coordination of H3K9me3. We also examine the relatively uncharacterized functions of SETDB2 with some comparison to the more well-known qualities of SETDB1. Finally, an emerging overall mechanism for the epigenetic maintenance of this transient phenotype is outlined by summarising the collective literature herein. CONCLUSION: A number of converging phenotypes outline a stress-responsive mechanism for SETDB1 and SETDB2 activation and subsequent increased survival, providing novel insights into epigenetic biology. A clearer understanding of how SETDB1/2-mediated transcriptional reprogramming can subvert treatment responses will be invaluable in improving length and efficacy of modern therapies. |
format | Online Article Text |
id | pubmed-6408861 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-64088612019-03-21 Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming Torrano, Joachim Al Emran, Abdullah Hammerlindl, Heinz Schaider, Helmut Clin Epigenetics Review BACKGROUND: A multitude of recent studies has observed common epigenetic changes develop in tumour cells of multiple lineages following exposure to stresses such as hypoxia, chemotherapeutics, immunotherapy or targeted therapies. A significant increase in the transcriptionally repressive mark trimethylated H3K9 (H3K9me3) is becoming associated with treatment-resistant phenotypes suggesting upstream mechanisms may be a good target for therapy. We have reported that the increase in H3K9me3 is derived from the methyltransferases SETDB1 and SETDB2 following treatment in melanoma, lung, breast and colorectal cancer cell lines, as well as melanoma patient data. Other groups have observed a number of characteristics such as epigenetic remodelling, increased interferon signalling, cell cycle inhibition and apoptotic resistance that have also been reported by us suggesting these independent studies are investigating similar or identical phenomena. MAIN BODY: Firstly, this review introduces reports of therapy-induced reprogramming in cancer populations with highly similar slow-cycling phenotypes that suggest a role for both IFN signalling and epigenetic remodelling in the acquisition of drug tolerance. We then describe plausible connections between the type 1 IFN pathway, slow-cycling phenotypes and these epigenetic mechanisms before reviewing recent evidence on the roles of SETDB1 and SETDB2, alongside their product H3K9me3, in treatment-induced reprogramming and promotion of drug resistance. The potential mechanisms for the activation of SETDB1 and SETDB2 and how they might arise in treatment is also discussed mechanistically, with a focus on their putative induction by inflammatory signalling. Moreover, we theorise their timely role in attenuating inflammation after their activation in order to promote a more resilient phenotype through homeostatic coordination of H3K9me3. We also examine the relatively uncharacterized functions of SETDB2 with some comparison to the more well-known qualities of SETDB1. Finally, an emerging overall mechanism for the epigenetic maintenance of this transient phenotype is outlined by summarising the collective literature herein. CONCLUSION: A number of converging phenotypes outline a stress-responsive mechanism for SETDB1 and SETDB2 activation and subsequent increased survival, providing novel insights into epigenetic biology. A clearer understanding of how SETDB1/2-mediated transcriptional reprogramming can subvert treatment responses will be invaluable in improving length and efficacy of modern therapies. BioMed Central 2019-03-08 /pmc/articles/PMC6408861/ /pubmed/30850015 http://dx.doi.org/10.1186/s13148-019-0644-y Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Review Torrano, Joachim Al Emran, Abdullah Hammerlindl, Heinz Schaider, Helmut Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming |
title | Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming |
title_full | Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming |
title_fullStr | Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming |
title_full_unstemmed | Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming |
title_short | Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming |
title_sort | emerging roles of h3k9me3, setdb1 and setdb2 in therapy-induced cellular reprogramming |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408861/ https://www.ncbi.nlm.nih.gov/pubmed/30850015 http://dx.doi.org/10.1186/s13148-019-0644-y |
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